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Search Results: 1 - 10 of 298098 matches for " Jyoti J Watters "
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Efficient isolation of live microglia with preserved phenotypes from adult mouse brain
Maria Nikodemova, Jyoti J Watters
Journal of Neuroinflammation , 2012, DOI: 10.1186/1742-2094-9-147
Abstract: After enzymatic digestion of brain tissues and myelin removal, CD11b+ cells were isolated using immunomagnetic separation, yielding highly purified microglia without astrocyte or neuronal contamination. We used three methods of myelin removal (30% Percoll, 0.9?mol/l sucrose and anti-myelin magnetic beads), and compared their effects on microglial viability and yield. To determine whether the isolation procedure itself activates microglia, we used flow cytometry to examine microglial properties in brain-tissue homogenates and isolated microglia from control and lipopolysaccharide (LPS) -treated mice.This method yielded a highly purified CD11b+ cell population with properties that reflected their in vivo phenotype. The viability and yield of isolated cells were significantly affected by the myelin removal method. Although the microglial phenotype was comparable in all methods used, the highest viability and number of CD11b+ cells was obtained with Percoll. Microglia isolated from LPS-treated mice displayed a pro-inflammatory phenotype as determined by upregulated levels of TNF-α, whereas microglia isolated from control mice did not.Immunomagnetic separation is an efficient method to isolate microglia from the CNS, and is equally suitable for isolating quiescent and activated microglia. This technique allows evaluation of microglial activities ex vivo, which accurately reflects their activities in vivo. Microglia obtained by this method can be used for multiple downstream applications including qRT-PCR, ELISA, Western blotting, and flow cytometry to analyze microglial activities in any number of CNS pathologies or injuries.
Expression of P2 nucleotide receptors varies with age and sex in murine brain microglia
Jessica M Crain, Maria Nikodemova, Jyoti J Watters
Journal of Neuroinflammation , 2009, DOI: 10.1186/1742-2094-6-24
Abstract: Microglia are the primary resident immune cell population in the central nervous system (CNS). They phagocytose debris following neuronal remodeling processes, help maintain CNS integrity, and perform neuronal support functions through the production of neurotrophins and growth factors [1]. Microglia also react to invading pathogens and CNS damage such as that resulting from physical injury, ischemia, and disease [2,3]. However, uncontrolled microglial activation and their resulting production of neurotoxic cytokines and reactive oxygen and nitrite species is thought to contribute to the pathology of many neurodegenerative disorders. Therefore, agents that function to reduce microglial inflammatory activities are currently being sought.Work from our laboratory and others' has pointed to a role for P2 purinergic receptors (P2Rs) in reducing microglial production of inflammatory mediators [4-6]. Purines are the endogenous ligands for most P2Rs, but pyrimidines and some nucleotide sugars can activate certain subtypes as well. The two major P2 receptor families are subdivided based on agonist specificities and proposed membrane topologies: the P2X receptors are ligand-gated cation channels composed of homo- or heterotrimeric P2X subunits, and the P2Y receptors are seven transmembrane, G protein-coupled receptors [7]. To date, there are seven known P2X receptor subtypes (P2X1–7) and eight P2Y receptor subtypes (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, P2Y14) however the P2Y11 receptor gene is absent from the rodent genome [8]. In microglia, nucleotides are important regulators of diverse cellular functions such as release of neuroprotective factors like BDNF [9-12], production of cytokines including TNF-α, IL-1β, and IL-6 [13-15], as well as phagocytic, chemotactic, and motility effects [16,17].Previous studies have evaluated the microglial expression of specific P2Rs in multiple CNS disease models [18-22], but few have addressed P2 receptor profiles in microglia fro
Chronic Intermittent Hypoxia Exerts CNS Region-Specific Effects on Rat Microglial Inflammatory and TLR4 Gene Expression
Stephanie M. C. Smith, Scott A. Friedle, Jyoti J. Watters
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0081584
Abstract: Intermittent hypoxia (IH) during sleep is a hallmark of sleep apnea, causing significant neuronal apoptosis, and cognitive and behavioral deficits in CNS regions underlying memory processing and executive functions. IH-induced neuroinflammation is thought to contribute to cognitive deficits after IH. In the present studies, we tested the hypothesis that IH would differentially induce inflammatory factor gene expression in microglia in a CNS region-dependent manner, and that the effects of IH would differ temporally. To test this hypothesis, adult rats were exposed to intermittent hypoxia (2 min intervals of 10.5% O2) for 8 hours/day during their respective sleep cycles for 1, 3 or 14 days. Cortex, medulla and spinal cord tissues were dissected, microglia were immunomagnetically isolated and mRNA levels of the inflammatory genes iNOS, COX-2, TNFα, IL-1β and IL-6 and the innate immune receptor TLR4 were compared to levels in normoxia. Inflammatory gene expression was also assessed in tissue homogenates (containing all CNS cells). We found that microglia from different CNS regions responded to IH differently. Cortical microglia had longer lasting inflammatory gene expression whereas spinal microglial gene expression was rapid and transient. We also observed that inflammatory gene expression in microglia frequently differed from that in tissue homogenates from the same region, indicating that cells other than microglia also contribute to IH-induced neuroinflammation. Lastly, microglial TLR4 mRNA levels were strongly upregulated by IH in a region- and time-dependent manner, and the increase in TLR4 expression appeared to coincide with timing of peak inflammatory gene expression, suggesting that TLR4 may play a role in IH-induced neuroinflammation. Together, these data indicate that microglial-specific neuroinflammation may play distinct roles in the effects of intermittent hypoxia in different CNS regions.
Increased GABAA Receptor ε-Subunit Expression on Ventral Respiratory Column Neurons Protects Breathing during Pregnancy
Keith B. Hengen, Nathan R. Nelson, Kyle M. Stang, Stephen M. Johnson, Stephanie M. Crader, Jyoti J. Watters, Gordon S. Mitchell, Mary Behan
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0030608
Abstract: GABAergic signaling is essential for proper respiratory function. Potentiation of this signaling with allosteric modulators such as anesthetics, barbiturates, and neurosteroids can lead to respiratory arrest. Paradoxically, pregnant animals continue to breathe normally despite nearly 100-fold increases in circulating neurosteroids. ε subunit-containing GABAARs are insensitive to positive allosteric modulation, thus we hypothesized that pregnant rats increase ε subunit-containing GABAAR expression on brainstem neurons of the ventral respiratory column (VRC). In vivo, pregnancy rendered respiratory motor output insensitive to otherwise lethal doses of pentobarbital, a barbiturate previously used to categorize the ε subunit. Using electrode array recordings in vitro, we demonstrated that putative respiratory neurons of the preB?tzinger Complex (preB?tC) were also rendered insensitive to the effects of pentobarbital during pregnancy, but unit activity in the VRC was rapidly inhibited by the GABAAR agonist, muscimol. VRC unit activity from virgin and post-partum females was potently inhibited by both pentobarbital and muscimol. Brainstem ε subunit mRNA and protein levels were increased in pregnant rats, and GABAAR ε subunit expression co-localized with a marker of rhythm generating neurons (neurokinin 1 receptors) in the preB?tC. These data support the hypothesis that pregnancy renders respiratory motor output and respiratory neuron activity insensitive to barbiturates, most likely via increased ε subunit-containing GABAAR expression on respiratory rhythm-generating neurons. Increased ε subunit expression may be critical to preserve respiratory function (and life) despite increased neurosteroid levels during pregnancy.
A role for tumor necrosis factor-α in ischemia and ischemic preconditioning
Orla Watters, John J O'Connor
Journal of Neuroinflammation , 2011, DOI: 10.1186/1742-2094-8-87
Abstract: As neurons are incapable of storing glucose, they rely on the cardiovascular system and astrocytes to deliver this source of energy. Thus, the depletion of oxygen (hypoxia) and glucose supply to the neuronal tissue during a stroke, will result in inadequate aerobic metabolism and failure of the cells to generate sufficient ATP levels required to meet metabolic demand [1]. Maintenance of Ca2+ homeostasis is lost due to insufficient ATP to fuel extrusion pumps, while the resting membrane potential is also disrupted due to dysfunction of the Na+/K+ ATPase pumps, leading to 'anoxic depolarisation' [2]. The resulting ionic imbalance within the neuronal and glial cells manifests in the development of tissue acidosis [3], cytotoxic oedema and ultimately necrosis [4]. The accumulation of cations in the cytosol contribute to transient depolarisation at the nerve terminals, which in turn triggers the activation of voltage-sensitive Na2+ channels, amplifying the accumulation of positive charge within the nerve terminal [5]. This increase in membrane potential will be detected by the voltage sensors on the intracellular domain of voltage-dependent Ca2+ channels (VDCC) causing a large influx of Ca2+ into the terminal promoting vesicular release of neurotransmitters and gliotransmitters such as glutamate and/or TNF-α from neuronal/glial cells, respectively [6], which at pathophysiological levels, induce cellular toxicity [7,8]. Extracellular levels of glutamate and TNF-α have been shown to remain elevated in the infarct region for hours up to days after a stroke, depending on the severity of the cerebral ischemic event [9-11]. Due to the complex nature of cross-communication between neuronal and glial cells, the contribution of glutamate and TNF-α to neurotoxicity during stroke is intricately interlinked, with both cell types responsible for the excessive elevation of these mediators to pathophysiological levels, by paracrine and/or autocrine signalling [12].TNF-α activity is med
Dynamic scaling in stick-slip friction
J. Feder,H. Nordhagen,W. A. Watters
Physics , 2005,
Abstract: We introduce a generalized homogeneous function to describe the joint probability density for magnitude and duration of events in self-organized critical systems (SOC). It follows that the cumulative distributions of magnitude and of duration are power-laws with exponents $\alpha$ and $\tau$ respectively. A power-law relates duration and magnitude (exponent $\gamma$) on the average. The exponents satisfy the dynamic scaling relation $\alpha=\gamma\tau$. The exponents classify SOC systems into universality classes that do not depend on microscopic details provided that both $\alpha<1$ and $\tau<1$. We also present new experimental results on the stick-slip motion of a sandpaper slowly pulled across a carpet that are consistent with our criteria for SOC systems. Our experiments, as well as experiments by others, satisfy our dynamic scaling relation. We discuss the relevance of our results to earthquake statistics.
To bind or not to bind - FoxA1 determines estrogen receptor action in breast cancer progression
Rebecca J Watters, Panayiotis V Benos, Steffi Oesterreich
Breast Cancer Research , 2012, DOI: 10.1186/bcr3146
Abstract: Patients with breast cancer that express estrogen receptor-alpha (ERα+) are candidates for endocrine therapies. Although endocrine therapies are among the most successful targeted therapies in oncology, a significant subset of ER+ breast cancers have become resistant to them. The activation of growth factor receptor (GFR) pathways has been identified as a possible culprit, and although ER is rarely mutated in endocrine-resistant tumors, it can be aberrantly activated by GFR signaling in a ligand-independent manner [1].Over the last few years, the application of chromatin immunoprecipitation (ChIP) coupled with massively parallel sequencing (ChIP-seq) enabled the identification of the ER cistrome in breast cancer cells [2]. By showing the following, the results brought an end to the dogma that ER binds primarily to the proximal promoters: (a) ER frequently binds distal enhancers [3], (b) the forkhead protein FoxA1 is necessary for ER-chromatin interactions [3-6], and (c) activation of GFR signaling results in the redirection of ER binding [7]. However, all previous studies, though highly informative, were performed in cell lines (primarily MCF-7 cells). Obtaining ChIP-seq results from primary breast tumors was the next step that everyone was eagerly awaiting.Ross-Innes and colleagues [8] analyzed ER ChIP-seq data from 15 ER+ tumors (eight with a good prognosis and seven with a poor prognosis) and three distant metastases. The authors found a core set of 484 ER-binding events present in at least 75% of all ER+ tumors (but not in the ER? controls). Intriguingly, ER-binding signal intensity was highest in metastatic samples and lowest in patients with good outcomes, suggesting that binding intensity may correspond to disease progression. Differential binding analysis found 1,192 ER-binding events that were stronger in the poor prognosis/metastasis group in comparison with the good outcome samples and found 599 binding events more prevalent in the good outcome tumors. Mo
Thermal and Dynamical Equilibrium in Two-Component Star Clusters
W. A. Watters,K. J. Joshi,F. A. Rasio
Physics , 1999, DOI: 10.1086/309220
Abstract: We present the results of Monte Carlo simulations for the dynamical evolution of star clusters containing two stellar populations with individual masses m1 and m2 > m1, and total masses M1 and M2 < M1. We use both King and Plummer model initial conditions and we perform simulations for a wide range of individual and total mass ratios, m2/m1 and M2/M1. We ignore the effects of binaries, stellar evolution, and the galactic tidal field. The simulations use N = 10^5 stars and follow the evolution of the clusters until core collapse. We find that the departure from energy equipartition in the core follows approximately the theoretical predictions of Spitzer (1969) and Lightman & Fall (1978), and we suggest a more exact condition that is based on our results. We find good agreement with previous results obtained by other methods regarding several important features of the evolution, including the pre-collapse distribution of heavier stars, the time scale on which equipartition is approached, and the extent to which core collapse is accelerated by a small subpopulation of heavier stars. We briefly discuss the possible implications of our results for the dynamical evolution of primordial black holes and neutron stars in globular clusters.
Long-distance communication and signal amplification in systemic acquired resistance
Jyoti Shah,Jürgen Zeier
Frontiers in Plant Science , 2013, DOI: 10.3389/fpls.2013.00030
Abstract: Systemic acquired resistance (SAR) is an inducible defense mechanism in plants that confers enhanced resistance against a variety of pathogens. SAR is activated in the uninfected systemic (distal) organs in response to a prior (primary) infection elsewhere in the plant. SAR is associated with the activation of salicylic acid (SA) signaling and the priming of defense responses for robust activation in response to subsequent infections. The activation of SAR requires communication by the primary infected tissues with the distal organs. The vasculature functions as a conduit for the translocation of factors that facilitate long-distance intra-plant communication. In recent years, several metabolites putatively involved in long-distance signaling have been identified. These include the methyl ester of SA (MeSA), the abietane diterpenoid dehydroabietinal (DA), the dicarboxylic acid azelaic acid (AzA), and a glycerol-3-phosphate (G3P)-dependent factor. Long-distance signaling by some of these metabolites also requires the lipid-transfer protein DIR1 (DEFECTIVE IN INDUCED RESISTANCE 1). The relative contribution of these factors in long-distance signaling is likely influenced by environmental conditions, for example light. In the systemic leaves, the AGD2-LIKE DEFENSE RESPONSE PROTEIN1 (ALD1)-dependent production of the lysine catabolite pipecolic acid (Pip), FLAVIN-DEPENDENT MONOOXYGENASE1 (FMO1) signaling, as well as SA synthesis and downstream signaling are required for the activation of SAR. This review summarizes the involvement and interaction between long-distance SAR signals and details the recently discovered role of Pip in defense amplification and priming that allows plants to acquire immunity at the systemic level. Recent advances in SA signaling and perception are also highlighted.
Evaluation of some Information Retrieval models for Gujarati Ad hoc Monolingual Tasks
Joshi Hardik J.,Pareek Jyoti
Computer Science , 2012,
Abstract: This paper describes the work towards Gujarati Ad hoc Monolingual Retrieval task for widely used Information Retrieval (IR) models. We present an indexing baseline for the Gujarati Language represented by Mean Average Precision (MAP) values. Our objective is to obtain a relative picture of a better IR model for Gujarati Language. Results show that Classical IR models like Term Frequency Inverse Document Frequency (TF_IDF) performs better when compared to few recent probabilistic IR models. The experiments helped to identify the outperforming IR models for Gujarati Language.
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